Systemic lupus erythematosus (SLE) is regarded as an autoimmune disease, in which abnormal hyperactivity of B lymphocytes and massive abnormal production of immunoglobulin gamma (IgG) auto-antibodies plays a key role. This pathological process results in sequestration and destruction of Ig-coated cells, fixation and cleaving of complement proteins, and release of chemotaxins, vasoac-tive peptides and destructive enzymes into tissues (Hahn B H. Systemic Lupus Erythematosus. In: Kasper D L, Braunwald E, Fauci A S, Hauser S L, Longo D L, Jameson, J L, editors. In: Harrison's Principles of Internal Medicine (16th edition). New York (US): McGraw-Hill; 2005. pp. 1960-1967).
SLE is characterized by diverse manifestations. In the course of the disease a total of 95% of patients complain of musculoskeletal disease, 80% show cutaneous lesions, 85% haematological disease, 60% neurological disorders, 60% cardiopulmonary disease, 30% to 50% renal disease, 40% gastrointestinal disease, 15% thrombosis and 15% ocular disease. The vast majority of the patients (95%) also suffer from systemic symptoms such as fatigue, malaise, fever, anorexia, and weight loss, which are present most of the time. Most patients experience disease periods of flares alternating with remissions. Permanent remissions (absence of symptoms with no treatment) are very rare. More than 50 years ago most patients diagnosed with SLE lived less than 5 years. Nowadays, 10 year survival is over 90%, mainly based on earlier diagnosis, symptomatic anti-inflammatory and immune-suppressive treatment. The common cause of death is infection as a result of immune-suppression (Hahn 2005).
Antimalarial, anti-inflammatory and immunosuppressive drugs have routinely been used in the treatment of SLE. Non-steroidal anti-inflammatories have been supplemented with corticosteroids when the symptoms become difficult to control. Further, active SLE, with major organ involvement, requires aggressive therapy with cyclophosphamide.
Up to now, there is no causative treatment available to cure SLE and/or improve patients' quality of life on a long term basis. However, recent advances in antibody technology and the further identification of factors underlying this autoimmune disease have opened up the possibility of using monoclonal antibodies as a treatment option. In particular, a favourable approach to treat SLE would be a specific treatment interacting or correcting the pathological immune response resulting in the massive overproduction of polyclonal auto-antibodies. Since the pathogenesis of SLE primarily involves dysregulated B cells, monoclonal antibodies capable of targeting B-cells are of special interest. As noted by Robak and Robak (Current Drug Targets, 2009, No. 10, pages 26-37) potential B-cell surface antigen targets are CD19, CD20, CD21 and CD22. Further, IL-10, IL-1ra, IL-12 (Capper et al., Clin. Exp. Immunol. 2004 November; 138(2):348-56), and IL-6 (Chun et al., J. Clin. Immunol. 2007 September; 27(5):461-6) are important cytokines in regulating immune response and are especially raised during flares in SLE patients. Plasma levels of IL-10 and auto-antibodies against double-stranded DNA (dsDNA) often mirror disease activity in patients with SLE. Raised IL-10 levels correlated with disease activity in SLE patients (Park et al., Clin. Exp. Rheumatol. 1998 May-June; 16(3):283-8). However, IL-10 is a cytokine with pleiotropic effects on the immune system and is also known to be involved in reducing proinflammatory responses.
Clinical trials with monoclonal antibodies have been conducted in SLE patients. In particular, several trials have involved the antibody Rituximab, a chimeric mouse anti-CD20 monoclonal antibody used for the treatment of non-Hodgkin's lymphoma. As noted by Robak and Robak (2009), the results of these trials show high activity of this antibody in SLE patients, and several new antibodies targeting CD20 have been developed; Ofatumumab, IMMU-106 and GA-101. Further clinical trials reporting activity of monoclonal antibodies in SLE have been completed with the anti-CD22 antibody, Epratuzumab, the anti-TNFα antibody, Infliximab, the anti-IL-10 antibody, B-N10 (Llorente et al., Arthritis Rheum. 2000 August; 43(8): 1790-800), the anti-CD40L antibodies, IDEC 131 and BG 9588, the BLYS inhibitor, Belimumab, the anti-IL6 receptor antibody, Toclimumab, and the anti-C5 antibody Eculizumab.
It is the aim of the present invention to provide further agents, and in particular antibodies, having utility in this area.
Accordingly the present invention provides a humanized or chimeric antibody or fragment thereof capable of binding to interleukin-10 (IL-10), wherein said antibody or fragment thereof is capable of being administered to a subject in the absence of an intolerable increase in the level of pro-inflammatory cytokines.
Since IL-10 represents an anti-inflammatory cytokine, one would expect upon blocking a dramatic increase of cytokines. For the murine IL-10 antibody, B-N10, where one can observe in unstimulated cell cultures (which reflects the in vivo situations in healthy individuals) an increase in proinflammatory cytokines such as IL-6 or TNF alpha. However, the inventors have surprisingly found that when the antibody of the present invention is applied to the cells in vitro, and administered in vivo, cytokine release is much lower. This lower cytokine release is advantageous as, as a result, the antibody of the present invention is more tolerable to individuals to which it is administered.